We plan a multi-center study to accurately describe the natural history of late kidney transplant failure, and to dissect out individual entities leading to late deterioration of function and to graft loss. Previous studies, and the current literature, attribute most chronic graft dysfunction (CGD) to a process called chronic rejection (CR) or chronic allograft nephropathy (CAN). Most recipients with this diagnosis have undergone biopsy late in their clinical course (if ever) at which time the histologic findings are non-specific. Our focus is to test the hypothesis that CGD is usually attributable to definable factors and not to a mysterious indefinable force known, as CR. Defining individual factors will permit future development of intervention trials. Our hypotheses are: 1) there are multiple, definable entities leading to CGD (and graft loss);2) these entities can be differentiated by clinical, radiological, serologic, and pathologic studies. 3) progression of CGD is due to an identifiable, currently operating injurious process and not the consequence of a past injury. Specific Aims of this grant are to: 1) determine, in a previously tx cross-sectional cohort, whether clinical, laboratory, and pathologic studies (conventional histology, immunohistology, special stains) at the time of initial graft dysfunction will allow definition of different clinico-pathologic entities (possibly with differing clinical courses);2) determine, in a prospective cohort, whether clinical, laboratory, and pathologic studies (conventional histology, immunohistology, special stains) at the time of initial graft dysfunction will confirm the definition of different entities (possibly with differing clinical courses);3) determine whether markers of fibrogenic activity and/or inflammation, the presence of anti-human leukocyte antibody (HLA) antibodies, or other clinical correlates can define specific pathophysiologic features that correlate with progression and with the rate of progression of CGD. Defining clinico-pathologic entities (and their individual clinical courses) will provide a knowledge base for future studies of CGD.